17alpha-alkyl-17beta-oxy-estratrienes and intermediate products for their production, use of the 17alpha-alkyl-17beta-oxy-estratrienes for the production of pharmaceutical agents as well as pharmaceutical preparations

ABSTRACT

The invention relates to 17α-alkyl-17β-oxy-estra-1,3,5(10)-trienes that have an antiestrogenic action with general formula I. In addition, the invention also relates to 17-oxo-estra-1,3,5(10)-trienes as well as 17β-hydroxy-estra-1,3,5(10)-trienes as intermediate products in the production of the estratrienes according to the invention. The invention also relates to the use of 17α-alkyl-17β-oxy-estratrienes for the production of pharmaceutical agents as well as pharmaceutical preparations that contain at least one 17α-alkyl-17β-oxy-estratriene as well as at least one pharmaceutically compatible vehicle.

[0001] The invention relates to 17α-alkyl-17β-oxy-estratrienes andintermediate products for their production, use of the17α-alkyl-17β-oxy-estratrienes for the production of pharmaceuticalagents as well as pharmaceutical preparations that contain thesecompounds.

[0002] The compounds according to the invention have antiestrogenicaction, i.e., these substances exert inhibiting actions relative toestrogens. Such substances have already been described extensively.

[0003] For example, compounds that have an antiestrogenic action areknown from EP 0 138 504 B1. These are then essentiallyestra-1,3,5(10)-triene derivatives, which are substituted in 3-position,i.a., with hydroxy or alkoxy, in 17β-position with hydroxy, and in17α-position, i.a., with hydrogen or alkyl. In 7α-position, thesecompounds also have an alkyl side chain that can be partiallyfluorinated and that can be interrupted by, i.a., amido, amino,amine-N-oxide, oxy, sulfanyl, sulfinyl and/or sulfonyl groups.

[0004] In WO 99/33855 A1, 11β-halogen-7α-substitutedestra-1,3,5(10)-trienes are described that can have hydroxy groups in3-position and in 17-position. The 7α-side chain is a partiallyfluorinated, optionally unsaturated hydrocarbon chain that isinterrupted by an amine-nitrogen atom or a sulfany, sulfinyl or sulfonylgroup.

[0005] Other compounds are described in WO 98/07740 A1. In thisconnection, these are substituted7α-(ξ-aminoalkyl)-estra-1,3,5(10)-trienes. These compounds preferablyhave a hydroxy, methoxy or acetyloxy group in 3-position and preferablya methyl or trifluoromethyl group in 17α-position and/or 17β-position.In 11β-position, a fluorine atom is preferably provided, and in7α-position, an alkyl side chain that is at least partially fluorinatedin the terminal position and that is interrupted by an amine-N atom andby a sulfanyl, sulfinyl or sulfonyl group is provided.

[0006] In WO 97/45441 A1,7α-(5-methylaminopentyl)-estra-1,3,5(10)-trienes are disclosed that havea hydroxy group in 3-position and in 17β-position. In 17α-position, amethyl or ethinyl group can be provided. The estratriene skeleton canalso be substituted in 2-position with a fluorine atom.

[0007] It has turned out that the known compounds in the applicationform a variety of biologically very active metabolites. The formation ofthese metabolites results in undesirable actions and thus in anuncontrollable spectrum of action. In particular, side effects can beadjusted or the desired primary action (antiestrogenic action) isuncontrollable by spontaneous formation of these metabolites. Inaddition, the compatibility of the known compounds in the case of oraladministration is unsatisfactory. It has turned out in particular thatthe known compounds promote the build-up of alveolar macrophages.

[0008] The object of this invention is therefore to find antiestrogeniccompounds whose metabolism can be controlled and that therefore formlittle or no biologically active metabolites. In addition, it is desiredthat the compatibility of the compounds that are sought is satisfactoryin the case of oral administration and in the case of whose dispensing,i.a., alveolar macrophages do not build up or at least build up only toa small extent.

[0009] This object is achieved by novel 17α-alkyl-17α-oxy-estratrienesaccording to claim 1, also by novel 17β-oxy-estratrienes according toclaim 16 as well as 17-oxo-estratrienes according to claim 18, which canbe used in each case as intermediate products for the production of17α-alky-17β-oxy-estratrienes according to the invention, also by theuse of 17α-alkyl-17β-oxy-estratrienes for the production ofpharmaceutical agents according to claim 20 and by the pharmaceuticalcompositions according to claim 21 that contain the compounds accordingto the invention.

[0010] The 17α-alkyl-17β-oxy-estratrienes according to the inventionhave general formula I:

[0011] Here, in particular:

[0012] Hal means F or Cl; this radical is bonded in 11β-position to theestratriene skeleton;

[0013] R ³ means hydrogen, C¹⁻-C₄-alkyl, -alkanoyl or, in more cyclicterms, C³⁻-C₇-ether with an O atom,

[0014] R^(17′) means hydrogen, C₁--C₄-alkyl and C₁--C₄-alkanoyl,

[0015] R¹⁷″ means C₁--C₄-alkyl, C₁-C₄-alkinyl as well as an at leastpartially fluorinated alkyl radical, whereby R¹⁷′ means —O in17β-position and R¹⁷″ in 17α-position is bonded to the estratrieneskeleton;

[0016] SK means —U—V—W—X—Y—Z—E, whereby this grouping is bonded via U in7α-position to the estratriene skeleton.

[0017] In the side chain, the symbols U, V, W, X, Y, Z and E have thefollowing meanings:

[0018] U represents either a straight-chain or branched-chain C₁--C₁₃-alkylene, -alkenylene or -alkinylene radical or the group A-B,whereby A is bonded to the estratriene skeleton and represents a

[0019] benzylidene radical that is bonded via —CH₂— to the estratrieneskeleton, a phenylene radical or a C₁--C₃-alkylaryl radical that isbonded via the alkyl group to the estratriene skeleton, and

[0020] B stands for a straight-chain or branched-chain C₁--C₁₃-alkylene,-alkenylene or -alkinylene radical, and whereby A and B also can beconnected to one another via an O atom.

[0021] V represents a CH₂ group or a C(O) group.

[0022] W is an N(R⁶) group or an N⁺(O⁻)(R⁶) group or an azolidinylenering or an azolidinylene-N-oxide ring,

[0023] whereby the azolidinylene ring or azolidinylene-N-oxide ringincludes at least one C atom of grouping X,

[0024] whereby R⁶ is also either H or CH₂—R⁷ or C(O)—R⁷, in which R₇ canmean, as follows:

[0025] a) Hydrogen or

[0026] b) A straight-chain or branched-chain, non-fluorinated or atleast partially fluorinated C₁--C₁₄-alkyl, -alkenyl or-alkinyl radical,which can be hydroxylated in one or more places and which can beinterrupted by one to three of the heteroatoms —O— and —S— and/or thegroupings —NR⁹—, in which R⁹ stands for hydrogen or a C₁--C₃-alkylradical, or

[0027] c) an unsubstituted or substituted aryl or heteroaryl radical, or

[0028] d) an unsubstituted or substituted C₃--C₁₀-cycloalkyl radical, or

[0029] e) an unsubstituted or substituted C₄--C₁₅-cycloalkylalkylradical, or

[0030] f) an unsubstituted or substituted C₇--C₂₀-aralkyl radical, or

[0031] g) an unsubstituted or substituted heteroaryl-C₁---C₆-alkylradical or

[0032] h) an unsubstituted or substituted aminoalkyl radical or abiphenyl radical,

[0033] X is preferably a straight-chain or branched-chainC₁--C₁₂-alkylene, -alkenylene or -alkinylene radical.

[0034] Y can be a direct bond between X and Z. Y can also mean thefollowing, however:

[0035] a) an SO_(n)—R¹⁰ group, only if W is an N⁺(O⁻)(R⁶) group or anazolidinylene-N-oxide ring and not an N(R⁶) group or an azolidinylenering, whereby n=0, 1 or 2, and whereby R¹⁰ represents a direct bondbetween SO_(n) and Z or a straight-chain or branched-chainC₁--C₆-alkylene, -alkenylene or -alkinylene radical,

[0036] b) or the group R¹¹ or O—R¹¹, whereby R¹¹ stands for

[0037] i) a straight-chain or branched-chain C₁--C₅-alkylene-,-alkenylene- or -alkinylene radical or for

[0038] ii) an unsubstituted or substituted aryl radical or heteroarylradical or for

[0039] iii) an unsubstituted or substituted C₃--C₁₀-cycloalkyl radicalor for

[0040] iv) an unsubstituted or substituted C₄--C₁₅-cycloalkylalkylradical or for

[0041] v) an unsubstituted or substituted C₇--C₂₀-aralkyl radical or for

[0042] vi) an unsubstituted or substituted heteroaryl-C₁---C₆-alkylradical, or

[0043] c) the grouping CH═CF or

[0044] d) the grouping HN—C(O)—NH—R¹²,

[0045] whereby R¹² stands for an unsubstituted or substituted aryleneradical and whereby R¹² is bonded to Z.

[0046] Z represents a direct bond between Y and E or a straight-chain orbranched-chain C₁--C₉-alkylene, -alkenylene or -alkinylene radical,which can be partially or completely fluorinated.

[0047] E is a CF₃ group or an at least partially fluorinated aryl group,in particular a phenyl group.

[0048] Moreover, preferably hydrogen atoms are bonded to positions 1, 2,4, 6 to 9 and 11 to 16 in the estratriene skeleton. In principle,however, the estratriene skeleton can also be modified, for example by ahydrocarbon bridge, for example a 15β,16β-methano group.

[0049] Hal in particular stands for fluorine.

[0050] R³ can be hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl and tert-butyl, a corresponding alkanoyl (acetyl, propionyl,butanoyl) or a cyclic ether. R³ in particular stands for hydrogen, CH₃,CH₃CO or C₅H₁₀O.

[0051] R^(17′) and R^(17″) are in particular methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl and tert-butyl, whereby R^(17′) inaddition can also be hydrogen, acetyl, propionyl and butanoyl, andwhereby in this case, the corresponding isomers can be included. Inaddition, R17″ can be ethinyl, 1-propinyl, 2-propinyl, 1-butinyl,2-butinyl and 3-butinyl as well as trifluoromethyl, pentafluoroethyl,heptafluoropropyl and nonafluorobutyl, whereby in this case, thecorresponding isomers are also included. R^(17′) is in particularhydrogen, CH₃ or CH₃CO. R^(7″) preferably stands for methyl, ethinyl andtrifluoromethyl.

[0052] U can be in particular a straight-chain or branched-chainalkylene radical and in particular a methylene, ethylene, propylene,butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene,undecylene, dodecylene or tridecylene radical. U preferably stands for(CH₂)_(p), whereby p is an integer from 2 to 10. In particular, U ispreferably a butylene, pentylene, hexylene or heptylene radical. U isquite especially preferably an n-butylene radical, i.e., in the formula(CH₂)_(p) for U, p=4.

[0053] In particular, V stands for CH₂. The grouping U-V thus can ben-pentylene in a quite preferred embodiment.

[0054] In particular, W stands for the amine-N-oxide N⁺(O⁻)(R⁶) or forthe amine N(R⁶), whereby R⁶ is preferably hydrogen or CH₂—R⁷, in which Rstands in particular for hydrogen or methyl or ethyl. R⁶ is thuspreferably hydrogen or a C₁--C₃-alkyl radical, thus in particular amethyl, ethyl, n-propyl or iso-propyl radical. In an especiallypreferred embodiment, W represents an N⁺(O⁻)(CH₃) group(N-methylamine-N-oxide).

[0055] X preferably stands for (CH₂)_(q), whereby q=0 or an integer from1 to 12, thus for a direct bond between W and Y or for a straight-chainor branched methylene, ethylene, propylene, butylene, pentylene,hexylene, heptylene, octylene, nonylene, decylene, undecylene ordodecylene radical. In an especially preferred embodiment, X is anethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, n-heptyleneor n-octylene radical.

[0056] In particular, Y can represent a direct bond between X and Z. Ifthis is the case, X stands for a longer alkylene chain, thus inparticular, X stands for n-hexylene, n-heptylene or n-octylene. In apreferred embodiment, Y can also be an SO_(n) group, whereby n=0, 1 or2, thus a sulfanyl group, a sulfinyl group or a sulfonyl group. If Y isan SO_(n) group, X represents a rather shorter alkylene chain, inparticular an n-propyl chain.

[0057] Z is preferably a direct bond between Y and E or a straight-chainor branched-chain C₁--C₇-alkylene radical, which can be at leastpartially fluorinated. In particular, Z can be a methylene, ethylene,propylene or butylene radical, which can be at least partiallyfluorinated. In particular, Z is difluoromethylene or a straight-chainalkylene radical, which is perfluorinated on one end, thus, for example,a 1,1-difluoroethylene, 1,1,2,2-tetrafluoro-n-propylene or1,1,2,2,3,3-hexafluoro-n-butylene radical. Alkylene radicals that carryonly two fluorine atoms on a terminal C-atom are especiallyadvantageous, whereby this CF₂ group is bonded to radical E. In thiscase, side chain SK is terminated with C₂F₅.

[0058] In particular, E stands for CF₃ or for pentafluorophenyl. Thegrouping Z-E thus preferably represents one of the groups that isselected from the group that comprises C₂F₅, C₃F₇ and C₄F₉ as well asC₆F₅.

[0059] According to this invention, pharmacologically compatible acidaddition salts as well as esters of 17α-alkyl-17β-oxy-estratrienes arealso included. The addition salts are the corresponding salts withinorganic and organic acids. As addition salts, in particular thehydrochlorides, hydrobromides, acetates, citrates, oxalates, tartratesand methanesulfonates are considered. If R³ and R^(17′) are hydrogen,such that a 3,17β-diol is present, the esters of these hydroxy compoundscan also be formed. These esters are preferably formed with organicacids, whereby the same acids as for forming the addition salts aresuitable, namely in particular acetic acid, but also higher carboxylicacids, such as, e.g., propionic, butyric, isobutyric, valeric,isovaleric or pivalic acid.

[0060] The novel 17α-alkyl-17β-oxy-estratrienes have several chiralcenters, for example also on an N atom that is optionally oxidized toform N-oxide. There are therefore several stereoisomeric forms of eachcompound in each case. The compounds of formula I can be present astautomers, stereoisomers or geometric isomers. The invention alsocomprises all possible isomers such as E- and Z-isomers, S- andR-enantiomers, diastereomers, racemates and mixtures thereof includingthe tautomeric compounds. All of these isomeric compounds are—even ifnot expressly indicated in each case—components of this invention. Theisomeric mixtures can be separated into enantiomers or E/Z-isomersaccording to commonly used methods, such as, for example,crystallization, chromatography or salt formation.

[0061] Especially suitable compounds as defined by the invention areestratrienes with general formula I, namely

[0062] 1)11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,9-heptafluorononyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide

[0063] 2)11β-Fluoro-7α-{5-[methyl(8,8,9,9,10,10,10-heptafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide

[0064] 3)(RS)-11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]-pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide

[0065] 4)11β-Fluoro-7α-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide

[0066] 5)11β-Fluoro-7α-{5-[methyl(9,9,10,10,10-pentafluorodecyl)amino]pentyl-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide

[0067] 6)11β-Fluoro-7α-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol

[0068] 7)11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol

[0069] 8)11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,9-heptafluorononyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol

[0070] 9)17α-Ethinyl-11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)-amino]pentyl1}-estra-1,3,5(10)-triene-3,17β-diol

[0071] 10)17α-Ethinyl-11β-fluoro-3-(2-tetrahydropyranoyloxy)-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-estra-1,3,5(10)-trien-17β-ol

[0072] 11)11β-Fluoro-3-(2-tetrahydropyranyloxy)-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-trien-17β-ol

[0073] 12)11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-trifluoromethylestra-1,3,5(10)-triene-3,17β-diol

[0074] 13)11β-Fluoro-7α-{5-[methyl(6,6,7,7,8,8,8-heptafluorooctyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol

[0075] 14)11β-Fluoro-7α-{5-[methyl(8,8,9,9,10,10,10-heptafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol

[0076] 15)11β-Fluoro-7α-{5-[methyl(6,6,7,7,8,8,9,9,10,10,10-undecafluorodecyl)amino]-pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol

[0077] 16)11β-Fluoro-7α-{5-[methyl(5,5,6,6,7,7,8,8,8-nonafluorooctyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol

[0078] 17)11β-Fluoro-7α-{5-[methyl(9,9,10,10,11,11,11-heptafluoroundecyl)amino]-pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol

[0079] 18)11β-Fluoro-7α-{5-[methyl(9,9,10,10,10-pentafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol

[0080] Physical properties of some of these compounds are indicated inTable 1.

[0081] The 17α-alkyl-17β-oxy-estratrienes according to the invention aredistinguished from known compounds primarily in that a halogen atom isbonded in 11α-position, and/or an alkyl radical is bonded in17α-position. In addition, preferred compounds in the 7α-side chain canhave an amine-N-oxide grouping.

[0082] In contrast to 3,17β-dihydroxy-estratrienes, which areunsubstituted in 17α-position, virtually no metabolites are formed fromthe 17α-alkyl-17β-oxy-estratrienes. according to the invention.Metabolites can also be biologically active. It has namely been revealedthat the estratrienes that are produced by oxidation of the hydroxygroup that is bonded in 17β-position, whereby a 17-oxo derivative isproduced, have very strong biological activity.

[0083] By blocking the 17α-position by an alkyl radical, especially by aC₁--C₄-alkyl group, this oxidation reaction is stopped, such that ametabolic variety is also suppressed. The estratrienes according to theinvention that are used as active ingredients therefore exhibit aspecies-independent effectiveness and activity. The advantage of thesecompounds therefore exists in that the full effectiveness of the activeingredient is achieved in a single compound.

[0084] For this reason, advantages arise in the development ofpharmaceutical agents, since owing to a lack of formation ofbiologically active metabolites, the effectiveness can more simply beascribed to certain structural principles, such that a targeted searchfor active ingredients is made possible.

[0085] In addition, the 17α-alkyl-17β-oxy-estratrienes according to theinvention inhibit the action of estradiol to approximately 100%. Theytherefore represent antiestrogens.

[0086] To study the effectiveness of the compounds according to theinvention, in-vivo tests were performed on infant rats. To this end, theuterus growth was performed with peroral (p. o.) administration of thepharmaceutical agent (test on antiestrogenic action).

[0087] The principle of this method consists in examining what influencethe administration of compounds that have an antiestrogenic action hasin the simultaneous administration of estrogens. In the case of rodents,the uterus reacts to the dispensing of estrogens namely with a weightincrease (both by proliferation and by water retention). This growth canbe inhibited in a dose-dependent manner by simultaneous administrationof compounds that have an antiestrogenic action.

[0088] For the tests, infant female rats with a weight of 35-45 g at thebeginning of the test were studied. Five to six animals were tested perdose. For the p.o. administration, the substances were dissolved in oneportion of ethanol (E) and were filled out with nine portions of peanutoil (EÖ). For acclimation, the young rats just dropped by the motherswere delivered one day before the beginning of treatment and immediatelysupplied with food—right in the cage. The animals were then treated incombination with 0.5 μg of estradiolbenzoate (EB) once daily for threedays. EB was always administered subcutaneously (s.c.), while the testsubstance was administered p.o. 24 hours after the last administration,the animals were weighed, killed, and the uteri were removed. The moistweights (less contents) were determined from the prepared uteri. Thefollowing control studies were performed: for a negative control, 0.2 mlof an E/EÖ mixture per animal and day was added. For a positive controlstudy, 0.5 μg of EB/0, 1 ml per animal and day, was administered.

[0089] From the relative organ weights (mg/100 g of body weight), theaverage values. with standard deviation (X±SD) as well as thesignificance of the differences in the control group (EB) in the DunnettTest (p<0.05) were determined for each group. The inhibition (in %)relative to the EB control was determined with a computer program. Therelative effectiveness of the test substances was calculated by acovariance and regression analysis.

[0090] Test results for selected compounds are reproduced in Table 2.Test results for the uterus growth with simultaneous administration of0.5 μg of EB/O, 1 ml s.c., as well as peroral dispensing of thecompounds that have an antiestrogenic action in an amount in the rangeof 0.03 mg/kg of body weight and 0.3 mg/kg of body weight are reproducedthere.

[0091] It can be seen from Table 2 that the antiestrogenic action isnearly 100% when a dosage of about 0.3 mg/kg in the case of peroraladministration was added.

[0092] The compounds according to the invention are as effective as oreven more effective than the corresponding compounds that are notsubstituted in 17α-position. Compared to the compounds that are notsubstituted in 17α-position, the estratrienes according to the inventionin addition have a better compatibility, such that the latter are to bepreferred. The better compatibility can be attributed in particular tothe fact that the formation of metabolites is largely limited.

[0093] Determination of metabolic.stability: in-vitro 17β-HSD test

[0094] 17β-HSD2 mediates the intestinal enzymatic dehydrogenization ofan OH group in 17-position of the sterane skeleton into a ketone group.

[0095] For this test, the following materials are used:

[0096] Na-Phosphate buffer: 100 mmol of Na₂HPO₄×2H₂O and 100 mmol ofNaH₂PO₄×H₂O

[0097] Test substance solution of

[0098]11β-Fluoro-7α-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol(compound 1, as a representative of the compounds of general formula I)and

[0099]11β-Fluoro-7α-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl-estra-1,3,5(10)-triene-3,17β-diol(compound 2): 15 μmol in MeOH (0.3 μmol in the test batch).

[0100] Cofactor solution: 2 ml of glucose-6-phosphate (160 mmol)/MgCl₂(80 mmol) mixture is added to 400 μl of aglucose-6-phosphate-dehydrogenase solution, and then 15.6 mg of NADP and13.4 mg of NAD are added.

[0101] Microsome solution: intestinal microsomes (In Vitro Technologies;protein content: 24 mg/ml; CYP450 content: 0.058 nmol/mg of protein)

[0102] In the water bath, it is thawed at 37° C. (˜60 seconds) anddiluted with Na-phosphate buffer to a concentration of 5 mg/ml ofprotein.

[0103] In each case, 170 μl/well of the buffer and 5 μl/well of the testsubstance solutions are introduced into the corresponding wells, wherebydouble values are applied for each measuring time (0, 10, 20, 30, 45 and60 minutes).

[0104] In each case, 250 μl of ice-cold MeOH is added to the 0-minutevalues. Then, 25 μl of microsome solution and 50 μl of cofactor solutionare added immediately to all wells. The samples of the 0-minute valuesare stored without incubation at ˜−20° C. for about 24 hours. The othersamples are incubated in each case for 10, 20, 30, 45 and 60 minutes at37° C., and the dehydrogenation reaction is stopped after these times bythe addition of 250 μl of ice-cold MeOH in each case. The samples arestored until measurement per LC/MS/MS at ˜−20° C., for about 24 hoursand centrifuged at 3000 rpm before analysis, whereby the supernatant ismeasured.

[0105] The concentrations of the test substances measured per LC/MS/MSand the resulting 17 ketone product are reproduced in FIGS. 2a-2 f.

[0106] Compound 1 is metabolically stable in intestinal microsomes butnot in liver microsomes, which indicates that different phase-1reactions occur in both tissues. The putative product of the17βHSD-reaction,11β-fluoro-7α-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}-estra-1,3,5(10)-trien-3-ol-17-one,compound 3, does not occur in any of the tissues, however. In contrastto this, compound 2, which does not have any 17 methyl group, isdegraded in intestinal microsomes, whereby the corresponding 17-ketoneis produced.

[0107] Consequently, the high metabolic stability of compound 1 can beexplained by the blocking of the 17βHSD reaction, which is completelystopped by a 17β-methyl group. It therefore has to be assumed from thisthat an alkyl group, for example a methyl group, or else an alkenyl oralkinyl group, for example an ethinyl group, in the vicinity of the17-OH group, prevents the intestinal (in contrast to the hepatic)oxidation thereof to ketone, surprisingly enough, which should have theresult of higher oral bioavailability.

[0108] In addition, the compounds according to the invention are thusdistinguished by an extraordinarily high bioavailability, such that highserum levels can be reached by the administration of the compoundsaccording to the invention to the affected patients. In connection withthe already mentioned high compatibility, a successFul and reliabletherapy can thus be performed since it is possible with the compoundsaccording to the invention to set a serum level of the active compoundthat has a sufficient distance to the effect level of the correspondingcompound. Effect level means the serum concentration of the activeingredient that is necessary at the least to achieve the desired effectin the respective indication.

[0109] The 17α-alkyl-17β-oxy-estratrienes with general formula Iaccording to the invention are suitable in particular for the productionof pharmaceutical agents. The invention therefore relates in addition tothe pharmaceutical preparation that in addition to at least one17α-alkyl-17β-oxy-estratriene with general formula I, which has thesubstituents Hal, R³, R^(17′), R^(17″), U, V, W, X, Y, Z and E accordingto the definitions above, contains at least one pharmaceuticallycompatible vehicle.

[0110] The pharmaceutical preparations or compositions according to theinvention are produced with commonly used solid or liquid vehicles ordiluents and commonly used pharmaceutical and technical adjuvantsaccording to the desired type of administration with a suitable dosagein a way that is known in the art. Preferred preparations consist of adispensing form that is suitable for oral, enteral, or parenteraladministration, for example i.p. (intraperitoneal), i.v. (intravenous),i.m. (intramuscular) or percutaneous, administration. Such dispensingforms are, for example, tablets, film tablets, coated tablets, pills,capsules, powders, creams, ointments, lotions, liquids, such as syrups,gels, injectable liquids, for example for i.p., i.v., i.m. orpercutaneous injection, etc. In addition, depot forms, such asimplantable preparations, as well as suppositories, are also suitable.In this case, depending on their type, the individual preparationsrelease to the body the estratrienes according to the inventiongradually or all at once in a short time.

[0111] For oral administration, capsules, pills, tablets, coated tabletsand liquids or other known oral forms for dispensing can be used aspharmaceutical preparations. In this case, the pharmaceutical agents canbe formulated in the way that they release the active ingredients eitherin a short time and pass on to the body or have a depot action; so thata longer-lasting, slow supply of active ingredients to the body isachieved. In addition to at least one estratriene, the dosage units cancontain one or more pharmaceutically compatible vehicles, for examplesubstances for adjusting the rheology of the pharmaceutical agent,surfactants, solubilizers, microcapsules, microparticles, granulates,diluents, binders, such as starches, sugar, sorbitol and gelatins, alsofillers, such as silicic acid and talc, lubricants, dyes, perfumes andother substances.

[0112] Corresponding tablets can be obtained, for example, by mixingactive ingredient with known adjuvants, for example inert diluents suchas dextrose, sugar, sorbitol, mannitol, polyvinyl pyrrolidone,explosives such as corn starch or alginic acid, binders such as starchor gelatin, lubricants such as carboxypolymethylene, carboxy methylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tabletscan also consist of several layers.

[0113] Coated tablets can be produced accordingly by coating cores thatare produced analogously to the tablets with, agents that are commonlyused in coated tablet coatings, for example polyvinylpyrrolidone orshellac, gum arabic, talc, titanium oxide or sugar. In this case, theshell of the coated tablet can also consist of several layers, wherebythe adjuvants that are mentioned above in the case of the tablets can beused.

[0114] Capsules that contain active ingredients can be produced, forexample, by the active ingredient being mixed with an inert vehicle suchas lactose or sorbitol and encapsulated in gelatin capsules.

[0115] The estratrienes according to the invention can also beformulated in the form of a solution that is intended for oraladministration and that in addition to the active estratriene containsas components a pharmaceutically compatible oil and/or apharmaceutically compatible lipophilic surfactant and/or apharmaceutically compatible hydrophilic surfactant and/or apharmaceutically compatible water-miscible solvent.

[0116] To achieve better bio-availability of the active ingredientsaccording to the invention, the compounds can also be formulated ascyclodextrin clathrates. To this end, the compounds are reacted with α-,β- or γ-cyclodextrin or derivatives thereof.

[0117] If creams, ointments, lotions and liquids that can be appliedtopically are to be used, the latter must be constituted so, that thecompounds according to the invention are fed to the body in adequateamounts. In these forms for dispensing, adjuvants are contained, forexample substances for adjusting the rheology of pharmaceutical agents,surfactants, preservatives, solubilizers, diluents, substances forincreasing the permeability of the estratrienes according to theinvention through the skin, dyes, perfumes and skin protection agents,such as conditioners and moisturizers. Together with the compoundsaccording to the invention, other active ingredients can also becontained in the pharmaceutical agent [Ullmanns Enzyklopädie dertechnischen Chemie [Ullmann's Encyclopedia of Technical Chemistry],Volume 4 (1953), pages 1-39; J. Pharm. Sci., 52, 918 ff. (1963); issuedby Czetsch-Lindenwald, Hilfsstoffe für Pharmazie und angrenzende Gehiete[Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind., 2, 72 ff(1961); Dr. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie,Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants forPharmaceutics, Cosmetics and Related Fields], Cantor A G,Aulendorf[Württ., 1971].

[0118] The substances according to the invention can also be used insuitable solutions, such as, for example, physiological common saltsolution, as infusion or injection solutions. For parenteraladministration, the active ingredients can be dissolved or suspended ina physiologically compatible diluent. As diluents, in particular oilysolutions, such as, for example, solutions in sesame oil, castor oil andcottonseed oil, are suitable. To increase solubility, solubilizers, suchas, for example, benzyl benzoate or benzyl alcohol, can be added.

[0119] To formulate an injectable preparation, any liquid vehicle can beused in which the compounds according to the invention are dissolved oremulsified. These liquids frequently also contain substances to regulateviscosity, surfactants, preservatives, solubilizers, diluents and otheradditives, with which the solution is set to isotonic. Other activeingredients can also be administered together with the estratrienes.

[0120] The estratrienes according to the invention can also be appliedin the form of a depot injection or an implant preparation, for examplesubcutaneously. Such preparations can be formulated in such a way that adelayed release of active ingredients is made possible. To this end,known techniques can be used, for example depots that dissolve oroperate with a membrane. Implants can contain as inert materials, forexample, biodegradable polymers or synthetic silicones, for examplesilicone gum. The estratrienes can also be incorporated in, for example,a patch, for percutaneous administration.

[0121] It is also possible to incorporate the substances according tothe invention in a transdermal system and thus to administer themtransdermally.

[0122] To achieve an improved transdermal skin flow that producestherapeutically effective blood levels, the compounds according to theinvention can also be incorporated in transdermal systems analogously towhat is described for other antiestrogens in WO 01/76608. Thesetransdermal systems are distinguished by a special ratio of 2penetration intensifiers, in particular lauric acid and propyleneglycol.

[0123] The dosage of the substances of general formula I according tothe invention is determined by the attending physician and depends on,i.a., the substance that is administered, the method of administration,the disease that is to be treated and the severity of the disease. Theamount of the compounds to be administered fluctuates within a widerange and can cover any effective amount Based on the condition to betreated and on the type of administration, the amount of administeredcompound can be 0.1-25 mg/kg of body weight, preferably 0.5-5 mg/kg ofbody weight, per day. In humans, this corresponds to a daily dose of5-1250 mg. The preferred daily dosage in humans is 50-200 mg. Thisapplies in particular to tumor therapy. The dose can be given as asingle dose to be administered once or divided into two or more dailydoses.

[0124] The compounds of general formula I represent, as alreadymentioned, compounds with very strong antiestrogenic action.

[0125] The compounds are suitable for therapy of estrogen-dependentdiseases, for example, breast cancer (second-line therapy oftamoxifen-resistant breast cancer; for adjuvant treatment of breastcancer instead of tamoxifen), endometrial carcinoma, prostatehyperplasia, anovulatory infertility and melanoma.

[0126] The compounds of general formula I can also be used as componentsin the products that are described in, i.a., EP 346 014 B1, whereby saidproducts contain an estrogen and a pure antiestrogen, namely forsimultaneous, sequential or separate use for the selective estrogentherapy of perimenopausal or postmenopausal women.

[0127] The compounds of general formula I can be used together withantigestagens (competitive progesterone antagonists) to treathormone-dependent tumors (EP 310 542 A).

[0128] Other indications in which the compounds of general formula I canbe used is male hair loss, diffuse alopecia, an alopecia caused bychemotherapy as well as hirsutism (Hye-Sun Oh, and Robert C. Smart,Proc. Natl. Acad. Sci. USA (93/1996) 12525-12530).

[0129] In addition, the compounds of general formula I can be used forthe production of medications for treating endometriosis.

[0130] The compounds of general formula I can also be used for theproduction of pharmaceutical compositions for male and female birthcontrol (male birth control: DE 195 10 862.0 A).

[0131] The estratrienes according to the invention can be producedanalogously to the known process:

[0132] In FIG. 1, a reaction diagram is reproduced, according to whichthe compounds according to the invention can be produced. In thisdiagram, the 17α-alkyl-17β-oxy-estratrienes according to the inventionare referred to with the term “17α-methyl-amine” and“17α-methyl-amine-oxide.” However, the compounds with the designation“17α-methyl” in 7α-position have a side chain without an amine grouping.The compounds that carry a hydroxy or alkoxy group in 17β-position, analkyl group in 17α-position as well as a7α-side chain with an aminegrouping are referred to as “17α-methyl-amine.” In a corresponding way,the compounds that are referred to as “17α-methyl-amine-oxide” are theamine-N-oxides according to the invention of the previously referenced“17α-methyl-amine” compounds.

[0133] If R³≠H, an etherification is performed with a reagent R³, inwhich X means a leaving group.

[0134] Compounds that are referred to as “17β-OH” are also estratrienesthat have a hydroxy group or alkoxy group in 17β-position but haveneither a 17α-alkyl grouping nor an amine grouping in the side chain in7α-position. Compounds that are referred to as “17-keto” areestratrienes that carry an oxo group in 17-position but do not carry anyamine grouping in the side chain in 7α-position. The other compoundsthat are referred to as “17β-OH-amine,” “17-keto-amine,”“17β-OH-amine-oxide” and “17-keto-amine-oxide” have correspondingsubstitution patterns.

[0135] In principle, all cited compounds, starting from the 17-oxocompound, can be produced. The production of the 17-oxo compounds isdescribed by way of example in, for example, WO 99/33855 A1. Derivativesother than the compounds that are disclosed expressly in this documentwith the same substitution pattern can be produced analogously. In thesame way, the estratrienes according to the invention can also beproduced starting from the 17β-hydroxy compounds or the 17β-alkoxycompounds (“17β-OH”). The production of these derivatives is alsoindicated in, for example, WO 99/33855 A1. In the same way, theproduction of the 17β-hydroxy compounds or 17β-alkoxy compounds as wellas the 17-oxo compounds with an amine grouping in the side chain in7α-position is disclosed in this document. If the production of thestarting compounds is not described, the starting compounds are knownand commercially available, or the compounds are synthesized analogouslyto the described processes. The production of a few precursors,intermediate products and products is described by way of example.

[0136] In the production of the substances according to the invention,for example, the following processes are employed (see also, in thisrespect, EP 0138 504 B1; WO 97/45441 A1; WO 98/07740 A1; WO 99/33855A1):

[0137] The 17α-alkyl-17β-oxy-estratrienes according to the invention canbe produced starting from the corresponding 17β-oxy-estratrienes(“17β-OH”). The synthesis of these starting substances is also describedin, for example, WO 97/45441 A1 and WO 98/07740 A1. The side chain in7α-position can be built up, for example, according to the-procedurethat is indicated in WO 98/07740 A1.

[0138] Then, the 17β-hydroxy compound or the 17β-alkoxy compound that isproduced can be oxidized with an amine grouping in the side chain in7α-position by oxidation to form the corresponding 17-oxo compound(“17-keto-amine”). To this end, commonly used oxidizing agents, forexample chromium(VI) compounds (Jones oxidation), nitric acid, manganesedioxide, selenium dioxide and SO₃ in pyridine can be used. The ketonescan also be produced by catalytic dehydrogenation with metallic copper,silver, copper chromate and zinc oxide at elevated temperature or bydehydrogenation with ketones, for example cyclohexanone, by Oppenaueroxidation. If the group reducing the side chain contains, for example, Sor SO groups, the latter can optionally be selectively reduced againafter an over-oxidation.

[0139] In another process variant, the 17β-oxy-estratrienes withoutamine-purging in the 7α-side chain can be oxidized directly to the17-oxo-estratrienes (“17-keto”), and the latter are then aminated in aknown way in the 7α-side chain.

[0140] Then, an alkyl group can be introduced in 17α-position. To thisend, commonly used nucleophilic alkylating reagents can be used, forexample Grignard reagents or alkyllithium compounds. In this reaction,the desired 17α-alkyl-17β-oxy-estratrienes are produced (“17α-methyl,”if a start is made from the corresponding 17β-hydroxy-estratrieneswithout an amine grouping in the side chain in 7α-position [“17β-OH”],or “17α-methyl-amine,” if a start is made from the corresponding7-hydroxy-estratrienes with an amine grouping in the side chain in17α-position [“17β-OH-amine”]). In addition, the 17-oxo-estratrienesthat are obtained as intermediate products can first be alkylated in aknown way and then aminated in the 7α-side chain.

[0141] If the amine-N-oxide compounds (“17β-OH-amine-oxide” or“17-keto-amine-oxide” or “17α-methyl-amine-oxide”) are to be produced,the corresponding estratrienes are oxidized with an amine grouping inthe 7α-side chain (“17β-OH-amine” or “17-keto-amine” or“17α-methyl-amine”), for example with hydrogen peroxide. In thisreaction, the secondary OH group in 17β-position is not oxidized.

[0142] In an alternative procedure for the production of the17α-alkyl-17β-oxy-estratrienes according to the invention, thepreviously-mentioned 17β-hydroxy-estratrienes with an amine grouping inthe side chain in 7α-position (“17β-OH-amine”) are also used as startingsubstances.

[0143] The latter are first reacted to form the correspondingamine-N-oxide compounds (“17β-OH-amine-oxide”), whereby, as indicatedabove, commonly used oxidizing agents, for example, hydrogen peroxide,are used.

[0144] Then, the formed amine-N-oxide compounds (“17β-OH-amine-oxide”)can be oxidized to the corresponding ketone (“17-keto-amine-oxide”),whereby the same oxidizing agents, as indicated above, can be used. Inthis case, the 17-oxo compounds with an amine-N-oxide grouping in the7α-side chain are produced.

[0145] For the production of the 17α-alkyl-17β-oxy-estratrienesaccording to the invention, the keto group is in turn reacted accordingto the instructions above with suitable nucleophilic alkylatingreagents. In this case, the 17α-alkyl-17β-oxy-estratrienes with anamine-N-oxide grouping in the 7α-side chain (“17α-methyl-amine-oxide”)are produced.

[0146] For the production of the 17α-alkyl-17β-oxy-estratrienesaccording to the invention, i.a., intermediate products with thefollowing general formula II are thus also formed, which also are thesubjects of this invention:

[0147] Here, in turn:

[0148] Hal=F or Cl, whereby this radical in 11β-position is bonded tothe estratriene skeleton,

[0149] R³ hydrogen, C₁--C₄-alkyl, C₁--C₄-alkanoyl or, in more cyclicterms, a C₃--C₇-ether with an O Atom,

[0150] R^(17′)=hydrogen, C₁--C₄-alkyl and C₁--C₄-alkanoyl, wherebyR^(17′)in 17β-position is bonded to the estratriene skeleton, and

[0151] SK=U—V—W—X—Y—Z—E, whereby this grouping is bonded to theestratriene skeleton via U in 7α-position, and whereby U, V, X, Y, Z andE have the meanings that are further indicated above, and W stands forN⁺(O⁻)(R⁶)— or for an azolidinylene-N-oxide ring, whereby theazolidinylene-N-oxide ring includes at least one C atom of grouping X,whereby R⁶ otherwise has the meaning that is further indicated above.

[0152] In positions 1, 2, 4, 6 to 9 and 11 to 16 on the estratrieneskeleton, hydrogen atoms are preferably bonded in turn, moreover: Inprinciple, the estratriene skeleton can also be modified, however, e.g.,by one hydrocarbon bridge, for example by a 15β,16β-methano group.

[0153] Especially preferred 17α-alkyl-17β-oxy-estratrienes with anamine-N-oxide grouping in the 7α-side chain with general formula II arethe following compounds:

[0154] X1)11β-Fluoro-7α-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}estra-1,3,5(10)-triene-3,17β-diolN-oxide

[0155] X2)11β-Fluoro-7α-[5-(methyl{3-[(2,3,4,5,6-pentafluorophenyl)sulfanyl]propyl}-amino)pentyl]estra-1,3,5(10)-triene-3,17β-doilN-oxide

[0156] X3)11β-Fluoro-7α-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfany]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-doilN-oxide

[0157] X4)11β-Fluoro-7α-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-diolN-oxide

[0158] X5)11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-triene-3,17β-doilN-oxide

[0159] X6)(S)-11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-doilN-oxide

[0160] X7)(R)-11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-doilN-oxide

[0161] X8)11β-FIuoro-7α-{5-[methyl(9,9,10,10,10-pentafluorodecyl)amino]pentyl}estra-1,3,5(10)-triene-3,17β-doilN-oxide.

[0162] Physical properties of these compounds are indicated in Table 3.

[0163] In addition, the 17-oxo-estratrienes with an amine-N-oxidegrouping that are formed in the production of the17α-alkyl-17β-oxy-estratrienes according to the invention in the 7α-sidechain as intermediate products are also subjects of this invention.These compounds have general formula III:

[0164] Here:

[0165] Hal means F or Cl, whereby this radical is bonded in 11β-positionto the estratriene skeleton,

[0166] R³ means hydrogen, C₁--C₄-alkyl, C₁--C₄-alkanoyl or, in morecyclic terms, a C₃--C₇-ether with an O atom, and

[0167] SK means U—V—W—X—Y—Z—E, whereby this grouping is bonded via U in7α-position to the estratriene skeleton and whereby U, V, X, Y, Z and Ehave the meanings that are further indicated above, and W stands for anN⁺(O⁻)(R⁶) group or for an azolidinylene-N-oxide ring, whereby theazolidinylene-N-oxide ring includes at least one C atom of grouping X,whereby R⁶ also has the meaning that is further indicated above.

[0168] In positions 1, 2, 4, 6 to 9 and 11 to 16 on the estratrieneskeleton, moreover, preferably hydrogen atoms are bonded in turn. Inprinciple, the estratriene skeleton can also be modified, but, e.g., bya hydrocarbon bridge, for example a 15β,16β-methano group.

[0169] Especially preferred 17-oxo-estratrienes with an amine-N-oxidegrouping in the 7α-side chain with general formula III are the followingcompounds:

[0170] Y111β-Fluoro-7α-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]propyl}-amino)pentyl]estra-1,3,5(10)-trien-3-ol-17-oneN-oxide

[0171] Y211β-Fluoro-7α-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]propyl}-amino)pentyl]estra-1,3,5(10)-trien-3-ol-17-oneN-oxide

[0172] Y311β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-estra-1,3,5(10)-trien-3-ol-17-oneN-oxide.

[0173] Physical properties of these compounds are indicated in Table 4.

[0174] The compounds of general formula II and the compounds of generalformula III are also compounds with antiestrogenic action. They cantherefore be used in principle in the types of indications indicatedabove for the compounds of general formula I.

[0175] Below, the process steps for the production of the compoundsaccording to the invention are described in more detail.

[0176] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The following preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

[0177] In the foregoing and in the following examples, all temperaturesare set forth uncorrected in degrees Celsius and, all parts andpercentages are by weight, unless otherwise indicated.

[0178] Process Variant 1.1

[0179] (Production of 17-oxo-estratrienes with amine-N-oxide grouping inthe side chain, starting from 17β-hydroxy-estratrienes with an aminegrouping in the side chain via the corresponding 17-oxoestratrienes):

[0180] a)11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]-pentyl}estra-1,3,5(10)-trien-3-ol-17-one(angle of rotation α_(D) of this compound (No. Z14) is indicated inTable 5)

[0181] 1.5 ml of ethyldiisopropylamine is added in drops at 10° C. to asolution of 1.23 g of pyridine sulfur trioxide complex in 10 ml of drieddimethyl sulfoxide. Then, 1.72 g of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-estra-1,3,5(10)-triene-3,17β-diol(compound No. Z9) as well as another 10 ml of dried dimethyl sulfoxideare added and stirred for 30 minutes at room temperature. Then, it isdiluted with ethyl acetate, washed with saturated sodium bicarbonatesolution, water and sodium chloride solution, dried on sodium sulfate,evaporated to the dry state in a vacuum and chromatographed on silicagel with dichloromethane/methanol.11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-trien-3-ol-17-one,[α]_(D)=+58.2°, in chloroform, is obtained.

[0182] b)11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]-pentyl}estra-1,3,5(10)-trien-3-ol-17-oneN-oxide

[0183] A solution of 0.5 g of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-trien-3-ol-17-one in 11ml of methanol and 11 ml of chloroform is mixed with 3.5 ml of 30%hydrogen peroxide solution and stirred for five days at roomtemperature. Then, it is mixed with sodium thiosulfate, added to water,extracted three times with dichloromethane, washed neutral, dried onsodium sulfate, evaporated to the dry state in a vacuum andchromatographed on silica gel with dichloromethane/methanol. 401 mg of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-trien-3-ol-17-oneN-oxide is obtained as a solid with a melting point of 84-86° C.;[α]_(D)=+53.6°, in chloroform.

[0184] c)11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]-pentyl}17β-methylestra-1,3,5(10)-triene-3,17-doilN-oxide

[0185] A suspension of 2.3 g of cerium(m) chloride in 23 ml oftetrahydrofuran is mixed at 0° C. with 3.19 ml of a 3-molarmethylmagnesium bromide solution in diethyl ether, and it is stirred for30 minutes. A solution of 250 mg of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-trien-3-ol-17-oneN-oxide in 5 ml of tetrahydrofuran is added in drops thereto and thenstirred for 24 hours at room temperature, mixed at 0° C. with 10 ml ofammonium chloride solution, extracted with ethyl acetate, washed withwater, dried with sodium sulfate, concentrated by evaporation in avacuum, taken up with 5 ml of methanol and 5 ml of chloroform, mixedwith 2 ml of 30% hydrogen peroxide solution, mixed and stirred for 5days at room temperature. Then, it is mixed with sodium thiosulfate,added to water, extracted three times with dichloromethane, washedneutral, dried on sodium sulfate, evaporated to the dry state in avacuum and chromatographed on silica gel with dichloromethane/methanol.165 mg of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-doilN-oxide with a melting point of 122° C. is obtained.

[0186] Process Variant 1.2:

[0187] (Production of 17-oxo-estratrienes with amine-N-oxide groupingsin the side chain, starting from 17β-hydroxy-estratrienes with aminegroupings in the side chain via the corresponding17β-hydroxy-estratrienes with amine-N-oxide groupings in the sidechain):

[0188] a)11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)-amino]pentyl}-estra-1,3,5(10)-triene-3,17-doilN-oxide

[0189] A solution of 50 g of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-estra-1,3,5(10)-triene-3,17β-diolin 500 ml of methanol and 500 ml of chloroform is mixed with 7.3 g ofsodium bicarbonate as well as 45 ml of 30% hydrogen peroxide solution,and it is stirred for 3 days at room temperature. Then, it is mixed withsodium thiosulfate, added to water, extracted three times withdichloromethane, washed neutral, dried on sodium sulfate, evaporated tothe dry state in a vacuum and absorptively precipitated from diethylether. 48.3 g of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-estra-1,3,5(10)-triene-3,17β-doilN-oxide with a melting point of 131.7° C. is obtained.

[0190] b)11β-FIuoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)-amino]pentyl}-estra-1,3,5(10)-trien-3-ol-17oneN-oxide

[0191] 1.5 ml of ethyldiisopropylamine is added in drops at 10° C. to asolution of 1.23 g of pyridine sulfur trioxide complex in 10 ml of drieddimethyl sulfoxide. Then, 1.62 g of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-estra-1,3,5(10)-triene-3,17β-diolN-oxide as well as another 10 ml of dried dimethyl sulfoxide are addedand stirred for 30 minutes at room temperature. Then, it is diluted withethyl acetate, washed with saturated sodium bicarbonate solution, waterand sodium chloride solution, dried on sodium sulfate, evaporated to thedry state in a vacuum and chromatographed on silica gel withdichloromethane/methanol. 1.32 g of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-estra-1,3,5(10)-trien-3-ol-17oneN-oxide is obtained as a solid with a melting point of 84-86° C.;[α]_(D)=+53.6° in chloroform.

[0192] Process Variant 2.1:

[0193] (Production of 17α-methyl-estratrienes with amine-N-oxidegroupings in the side chain, starting from 17-oxo-estratrienes withamine groupings in the side chain via the corresponding17-oxo-estratrienes with amine-N-oxide groupings in the side chain):

[0194] a)11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]-pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol(physical properties of this compound (No. 7) are indicated in Table 1)

[0195] A suspension of 230 g of cerium(III) chloride in 2.31 oftetrahydrofuran is mixed at 0° C. with 320 ml of a 3-molarmethylmagnesium bromide solution in diethyl ether and stirred for 30minutes. A solution of 25 g of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-trien-3-ol-17-one(angle of rotation α_(D) of this compound (No. Z14) is indicated inTable 5) in 250 ml of tetrahydrofuran is added in drops thereto and thenstirred for 24 hours at room temperature, mixed at 0° C. with ammoniumchloride solution, extracted with ethyl acetate, washed with water,dried with sodium sulfate, concentrated by evaporation in a vacuum andchromatographed on silica gel with dichloromethane/methanol. 19.1 g of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolwith a melting point of 82-85° C. and [α]_(D)=+21.8° in chloroform isobtained.

[0196] b)11β-Fluoro-7β-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)-amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide

[0197] A solution of 18 g of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolin 180 ml of chloroform and 180 ml of methanol is mixed with 2.57 g ofsodium bicarbonate and 16.2 ml of a 30% hydrogen peroxide solution, andit is stirred for 48 hours at room temperature. Then, it is diluted withdichloromethane, washed with water and sodium thiosulfate solution,dried on sodium sulfate, evaporated to the dry state in a vacuum andabsorptively precipitated with diethyl ether. 18.4 g of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide with a melting point of 122° C. is obtained.

[0198] Process Variant 2.2:

[0199] (Production of 17α-methyl-estratrienes with amine groupings inthe side chain, starting from 17-oxo-estratrienes via the corresponding17α-methyl-estratrienes):

[0200] a)7α-(5-Bromopentyl)-11β-fluoro-17α-methylestra-1,3,5(10)-triene-3,17β-diol

[0201] A suspension of 46.8 g of cerium(III) chloride in 0.47 1 oftetrahydrofuran is mixed at 0° C. with 63.8 ml of a 3-molarmethylmagnesium bromide solution in diethyl ether, and it is stirred for1 hour. A solution of 25 g of7α-(5-bromopentyl)-11β-fluoro-estra-1,3,5(l0)-trien-3-ol-17-one in 200ml of tetrahydrofuran is added in drops thereto and then stirred for 28hours at room temperature, mixed at 0° C. with ammonium chloridesolution, extracted with ethyl acetate, washed with water, dried withsodium sulfate, concentrated by evaporation in a vacuum andchromatographed on silica gel with dichloromethane/methanol. 15.1 g of7α-(5-bromopentyl)-11β-fluoro-17α-methylestra-1,3,5(10)-triene-3,17β-doilwith a melting point of 48.6° C. is obtained.

[0202] b)11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]-pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-doil(physical properties of this compound (No. 7) are indicated in Table 1)

[0203] A solution of 18 g of7α-(5-bromopentyl)-11β-fluoro-17α-methylestra-1,3,5(10)-triene-3,17β-diolin 180 ml of dimethylformamide is mixed with 15.9 g of(7,7,8,8,9,9,10,10,10-nonafluorodecyl)-methyl-amine and 5 g of sodiumcarbonate and then stirred. for 8.5 hours at a bath temperature of 80°C. Then, it is added to water, extracted with ethyl acetate, washed withwater and saturated sodium chloride solution, dried on sodium sulfate,concentrated by evaporation in a vacuum and chromatographed on silicagel with dichloromethane/methanol. 22.9 g of11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolwith a melting point of 82-85° C. and [α]_(D)=+21.8° in chloroform isobtained.

[0204] Additional compounds according to the invention can be producedanalogously. To this end, additional intermediate products are presentedin Table 5. In addition, physical properties of these compounds are alsopartially indicated. TABLE 1 Melting Angle of Point Rotation [° C.]α_(D) ¹) 1 11β-Fluoro-7α-{5- 152-154 [methyl(7,7,8,8,9,9,9-heptafluorononylyl)amino] pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-3-diol N-oxide 2 11β-Fluoro-7α-{5-[methyl(8,8,9,9,10,10,10- 137.7+31° heptafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol N-oxide 3(RS)-11β-Fluoro-7α-{5-[methyl 122 +29.6°(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)- triene-3,17β-diol N-oxide 411β-Fluoro-7α-{5-[methyl(8,8,9,9,9- 148.5 +25.3°pentafluorononylyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol N-oxide 511β-Fluoro-7α-{5-[methyl(9,9,10,10,10- 118-120 +26°pentafluorodecyl)amino]pentyl-17α-methylestra-1,3,5(10)-triene-3,17β-diol N-oxide 611β-Fluoro-7α{5-[methyl(8,8,9,9,9- 68-71 +32°pentafluorononyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol 7 11β-Fluoro-7α-{5-[methyl 82-85+21.8 (7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)- triene-3,17β-diol 811β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,9- 138 +29.8°heptafluorononyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol 917α-Ethinyl-11β-fluoro-7α-{5-[methyl 128-130 +13.1°(7,7,8,8,9,9,10,10,10-nonafluorodecyl) amino]pentyl}-estra-1,3,5(10)-triene-3,17β-diol 10 17α-Ethinyl-11β-fluoro-3-(2- −18.1°tetrahydropyranolyloxy)-7α-{5-[methyl (7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-estra-1,3,5 (10)-trien-17β-ol 1111β-Fluoro-3-(2-tetrahydropyranyloxy)- +26.9°7α-{5-[methyl(7,7,8,8,9,9,10,10,10- nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-trien-17β-ol 12 11β-Fluoro-7α-{5-[methyl +24.6°(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-trifluoromethylestra- 1,3,5(10)-triene-3,17β-diol 1311β-Fluoro-7α-{5-[methyl(6,6,7,7,8,8,8- 96.3 +38.8°heptafluorooctyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol 1411β-Fluoro-7α-{5-[methyl(8,8,9,9,10,10,10- 137 +24.6°heptafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5,(10)-triene-3,17β-diol 15 11β-Fluoro-7α-{5-[methyl112.6 +21.3° (6,6,7,7,8,8,9,9,10,10,10-undecafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5, (10)-triene-3,17β-diol 1611β-Fluoro-7α-{5-[methyl(5,5,6,6,7,7,8,8,8-nonafluorooctyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol 17 11β-Fluoro-7α-{5-[methyl(9,9,10,10,11,11,11-heptafluoroundecyl)amino]pentyl}-17α-methylestra-1,3,5(10)- triene-3,17βdiol 1811β-Fluoro-7α-{5-[methyl(9,9,10,10,10- 88-90 +32.5°pentafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol

[0205] TABLE 2 Antiuterotropic Action % % s.c. Inhib. p.o. Inhib. 3(RS)-11β-Fluoro-7α-{5- 0.3 76 [methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol N-oxide 7 11β-Fluoro-7α-{5- 0.0359 [methyl(7,7,8,8,9,9,10,10,10- nonafluorodecyl)amino]pentyl}17α-methylestra-1,3,5(10)-triene-3,17β-diol 8 11β-Fluoro-7α-{5- 0.3 94[methyl(7,7,8,8,9,9,9- heptafluorononyl)amino]pentyl}-17α-methylestra-1,3,5(10)triene-3,17β-diol

[0206] TABLE 3 Melting Angle of Point Rotation [° C.] α_(D) ¹) X111β-Fluoro-7α-{5-[methyl(8,8,9,9,9- 158-160 +33.6°pentafluorononyl)amino]pentyl}estra- 1,3,5(10)-triene-3,17β-diol N-oxideX2 11β-Fluoro-7α-[5-(methyl{3-[(2,3,4,5,6-pentafluorophenyl)sulfanyl]propyl}amino)- pentyl]estra-1,3,5(10)-triene-3,17β-diol N-oxide X3 11β-Fluoro-7α-[5-(methyl{3-[(4,4,5,5,5- 114-116pentafluoropentyl)sulfanyl]propyl]amino)-pentyl]estra-1,3,5(10)-triene-3,17β-diol N-oxide X411β-Fluoro-7α-[5-(methyl{3-[(4,4,5,5,5- 103-105pentafluoropentyl)sulfinyl]propyl}-amino)pentyl]estra-1,3,5(10)-triene-3,17β-3-diol N-oxide X5 11β-Fluoro-7α-{5-147-150 +30.2° [methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra 1,3,5(10)-triene-3,17β-diol N-oxideX6 (S)-11β-Fluoro-7α-{5- 128.5 +32.5° [methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol N-oxide X7 (R)-11β-Fluoro-7α-{5-144.0 +31.3° [methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol N-oxide X811β-Fluoro-7α-{5-[methyl(9,9,10,10,10-  99-101 +28.5°pentyfluorodecyl)amino]pentyl}estra- 1,3,5(10)-triene-3,17-3-diolN-oxide

[0207] TABLE 4 Melting Angle of Point Rotation [° C.] α_(D) ¹) Y111β-Fluoro-7α-[5-(methyl{3-[(4,4,5,5,- +45.6°pentafluoropentyl)sulfinyl]propyl}amino)-pentyl]estra-1,3,5(10)-trien-3-ol-17-one N-oxide Y211β-Fluoro-7α-[5-(methyl{3-[(4,4,5,5,5- +52.8°pentafluoropentyl)sulfanyl]propyl}amino)-pentyl]estra-1,3,5(10)-trien-3-ol-17-one N-oxide Y3 11β-Fluoro-7α-{5-84-86 +53.6° [methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra- 1,3,5(10)-trien-3-ol-17-one N-oxide

[0208] TABLE 5 Melting Angle of Point Rotation [° C.] α_(D) ¹) Z111β-Fluoro-7α-{5-[methyl(8,8,9,9,9- pentafluorononyl)amino]pentyl}estra-1,3,5(10)-triene-3,17β-diol Z2 11β-Fluoro-7α-{5-methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}estra- 1,3,5(10)-trien-3-ol-17-one Z311β-Fluoro-7α-{5-methyl (3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)amino]pentyl}estra- 1,3,5(10)-trien-3-ol-17-one Z411β-Fluoro-7α-{5-[methyl(9,9,10,10,10- +48.4°pentafluorodecyl)amino]pentyl}estra- 1,3,5(10)-trien-3-ol-17-one Z511β-Fluoro-7α-{5-[methyl(9,9,10,10,10-pentafluorodecyl)amino]pentyl}estra- 1,3,5(10)-triene-3,17β-diol Z611β-Fluoro-7α-{5-[methyl (3,3,4,4,5,5,6,6,6-nonafluorohexyl)amino]pentyl}estra- 1,3,5(10)-triene-3,17β-diol Z711β-Fluoro-7α-{5-[methyl (4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)amino]pentyl}- estra-1,3,5(10)-triene-3,17β-diol Z811β-Fluoro-7α-{5-[methyl(7,7,8,8,8- pentafluorooctyl)amino]pentyl}estra-1,3,5(10)-triene-3,17β-diol Z9 11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10- nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-triene-3,17β-diol Z10 11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluorododecyl)amino]-pentyl}estra- 1,3,5(10)-triene-3,17β-diolZ11 11β-Fluoro-7α-{5-[methyl (4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluorotetradecyl) amino]pentyl}estra-1,3,5(10)-triene-3,17β-diol Z12 11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,11,11,12,12,13,13,14,14,14-heptadecafluorotetradecyl) amino]pentyl}estra-1,3,5(10)-triene-3,17β-diol Z13 11β-Fluoro-7α-{5-[methyl (5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorodecyl)amino]pentyl}- estra-1,3,5(10)-triene-3,17β-diol Z1411β-Fluoro-7α-{5-[methyl +58.2° (7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)- trien-3-ol-17-one Z1511β-Fluoro-3-methoxy-7α-{5-[methyl +39.2°(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]-pentyl}estra-1,3,5(10)-trien-17β-ol Z1611β-Fluoro-3-methoxy-7α-{5-[methyl +55.9°(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]-pentyl}estra-1,3,5(10)-trien-17-one Z1717β-Acetyloxy-11β-fluoro-7α-{5-[methyl +21.0° (7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]- pentyl}estra-1,3,5(10)-trien-3-ol Z1811β-Fluoro-7α-{5-[methyl +66.1° (7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra- 1,3,5(10)-triene-3-(2-tetrahydropyranoyloxy)-17-one Z19 3-tert-Butanoyloxy-11β-fluoro-7α-{5-+31.2° [methyl(7,7,8,8,9,9,10,10,10,-nonafluorodecyl)-amino]pentyl}estra- 1,3,5(10)-trien-17β-ol Z203-Acetyloxy-11β-fluoro-7α-{5-[methyl +33°(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]-pentyl}estra-1,3,5(10)-trien-17β-ol Z21 11β-Fluoro-7α-{5-[methyl(6,6,7,7,8,8,9,9,9- nonafluorononyl)amino]pentyl}estra-1,3,5(10)-triene-3,17β-diol Z22 11β-Fluoro-7α-{5-[methyl(8,8,9,9,10,10,11,11,11- nonafluoroundecyl)amino]pentyl}estra-1,3,5(10)-triene-3,17β-diol Z23 11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,9-125.0 heptafluorononylyl)amino]pentyl}estra- 1,3,5(10)-triene-3,17β-diolZ24 11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,9- +70.2°heptafluorononyl)amino]pentyl}estra- 1,3,5(10)-trien-3-ol-17-one Z2511β-Fluoro-7α-{5-[methyl(6,6,7,7,8,8,8- +71.6°heptafluorooctyl)amino]pentyl}estra- 1,3,5(10)-trien-3-ol-17-one Z2611β-Fluoro-7α-{5-[methyl(6,6,7,7,8,8,8- 112.8 +42.6°heptafluorooctyl)amino]pentyl}estra- 1,3,5(10)-triene-3,17β-diol Z2711β-Fluoro-7α-{5-[methyl +56.2°(8,8,9,9,10,10,10-heptafluorodecyl)amino]pentyl}estra-1,3,5(10)-trien-3-ol-17-one Z28 11β-Fluoro-7α-{5-[methyl104 +34.9° (8,8,9,9,10,10,10-heptafluorodecyl)amino]pentyl}estra-1,3,5(10)-triene-3,17β-diol Z29 11β-Fluoro-7α-{5-[methyl+64.6° (6,6,7,7,8,8,9,9,10,10,10- undecafluorodecyl)amino]-pentyl}estra-1,3,5(10)-trien-3-ol-17-one Z30 11β-Fluoro-7α-{5-[methyl 94-96 +36.8°(6,6,7,7,8,8,9,9,10,10,10- undecafluorodecyl)amino]-pentyl}estra-1,3,5,(10)-triene-3,17β-diol Z31 11β-Fluoro-7α-{5-[methyl(5,5,6,6,7,7,8,8,8- nonafluorooctyl)amino]pentyl}estra-1,3,5(10)-trien-3-ol-17-one Z32 11β-Fluoro-7α-{5-[methyl(5,5,6,6,7,7,8,8,8- nonafluorooctyl)amino]pentyl}estra-1,3,5(10)-triene-3,17β-diol Z33 11β-Fluoro-7α-{5-[methyl(9,9,10,10,11,11,11- heptafluoroundecyl)amino]pentyl}estra1,3,5(10)-trien-3-ol-17-one Z34 11β-Fluoro-7α-{5-[methyl(9,9,10,10,11,11,11-heptafluoroundecyl)amino]pentyl}estra-1,3,5(10)-triene- 3,17β-diol

[0209] The entire disclosure of all applications, patents andpublications, cited herein and of corresponding German Application No.101 59 217.5, filed Nov. 27, 2001 is incorporated by reference herein.

[0210] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0211] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. 17α-Alkyl-17β-oxy-estratrienes with general formula I

in which Hal stands for F or Cl, and is bonded to the estratrieneskeleton in 11β-position, R³ stands for hydrogen, C₁--C₄-alkyl,C₁--C₄-alkanoyl or a cyclic C₃--C₇-ether with an O atom, R^(17′)standsfor hydrogen, C₁--C₄-alkyl or C₁--C₄-alkanoyl, R^(17″)stands forC₁--C₄-alkyl, C₁--C₄-alkyl, C₁--C₄-alkinyl as well as for at leastpartially fluorinated C₁--C₄-alkyl radicals, whereby R^(17′)—O in17β-position and R17″ in 17α-position are bonded to the estratrieneskeleton, and SK stands for the grouping U—V—W—X—Y—Z—E, whereby thisgrouping is bonded to the estratriene skeleton via U in 7α-position, inwhich U represents either a straight-chain or branched-chainC₁--C₁₃-alkylene-, -alkenylene- or -alkinylene radical or the group A-B,whereby A is bonded to the estratriene skeleton and represents abenzylidene radical that is bonded via —CH₂— to the estratrieneskeleton, a phenylene radical, or a C₁--C₃-alkylaryl radical that isbonded via the alkyl group to the estratriene skeleton, and B stands fora straight-chain or branched-chain C₁--C₁₃-alkylene-, -alkenylene- or-alkinylene radical, and whereby A and B can also be connected to oneanother via an O atom, in which V further represents a CH₂— or a C(O)group, in which W further is an N(R⁶)— group or an N⁺(O⁻)(R⁶) group oran azolidinylene ring or an azolidinylene-N-oxide ring, whereby theazolidinylene ring or azolidinylene-N-oxide ring includes at least one Catom of grouping X, whereby R⁶ further is either H or CH₂—R⁷ or C(O)—R⁷,in which R⁷ can mean the following: a) hydrogen or b) a straight-chainor branched-chain, non-fluorinated or at least partially fluorinatedC₁--C₁₄-alkyl-, -alkenyl- or -alkinyl radical, which can be hydroxylatedin one or more places and can be interrupted by one to three of theheteroatoms —O—and —S—and/or the groupings —NR⁹—, in which R⁹ stands forhydrogen or a C₁--C₃-alkyl radical, or c) an unsubstituted orsubstituted aryl- or heteroaryl radical or d) an unsubstituted orsubstituted C₃--C₁₀-cycloalkyl radical or e) an unsubstituted orsubstituted C₄--C₁₅-cycloalkylalkyl radical or f) an unsubstituted orsubstituted C₇--C₂₀-aralkyl radical or g) an unsubstituted orsubstituted heteroaryl-C ₁---C₆-alkyl radical or h) an unsubstituted orsubstituted aminoalkyl radical or a biphenyl radical, in which X furtheris a straight-chain or branched-chain C₁--C₂-alkylene-, -alkenylene- or-alkinylene radical, in which Y further is a direct bond between X and Zor can mean the following: a) an SO_(n)—R¹⁰ group, whereby n=0, 1 or 2,only if W is an N⁺(O⁻)(R⁶) group or an azolidinylene-N-oxide ring andnot an N(R⁶) group or an azolidinylene ring, whereby R¹⁰ represents adirect bond between SO_(n) and Z or a straight-chain or branched-chainC₁--C₆-alkylene-, -alkenylene- or -alkinylene radical, or b) the groupR¹¹ or O—R¹¹, whereby R¹¹ stands for i) a straight-chain orbranched-chain C₁--C₅-alkylene-, -alkenylene- or -alkinylene radical orfor ii) an unsubstituted or substituted aryl radidal or heteroarylradical or for iii) an unsubstituted or substituted C₃--C₁₀-cycloalkylradical or for iv) an unsubstituted or substitutedC₄--C₁₅-cycloalkylalkyl radical or for v) an unsubstituted orsubstituted C₇--C₂₀-aralkyl radical or for vi) an unsubstituted orsubstituted heteroaryl-C₁---C₆-alkyl radical, or c) the grouping CH═CFor d) the grouping HN—C(O)—NH—R¹², whereby R¹² stands for anunsubstituted or substituted arylene radical, and whereby R ¹² is bondedto Z, and in which Z further is a direct bond between Y and E or astraight-chain or branched-chain C₁--C₉-alkylene-, -alkenylene- or-alkinylene radical, which can be partially or completely fluorinated,and in which E further is a CF₃ group or an at least partiallyfluorinated aryl group, whereby pharmacologically compatible acidaddition salts as well as esters are also included.
 2. Estratrienesaccording to claim 1, characterized in that R³ stands for hydrogen, CH₃,CH₃CO or C₅H₁₀O.
 3. Estratrienes according to one of the precedingclaims, wherein R^(17′) stands for hydrogen, CH₃ or CH₃CO, and whereinR^(17″) stands for methyl, ethinyl or trifluoromethyl.
 4. Estratrienesaccording to one of the preceding claims, wherein Hal stands forfluorine.
 5. Estratrienes according to one of the preceding claims,wherein U stands for (CH₂)_(p), whereby p is an integer from 2 to
 10. 6.Estratrienes according to one of the preceding claims, wherein p=4. 7.Estratrienes according to one of the preceding claims, wherein V standsfor CH₂.
 8. Estratrienes according to one of the preceding claims,wherein W stands for N(R⁶)— or N⁺(O⁻)(R⁶), whereby R⁶ is hydrogen or aC₁--C₃-alkyl radical.
 9. Estratrienes according to one of the precedingclaims, wherein R⁶ stands for methyl.
 10. Estratrienes according to oneof the preceding claims, wherein X stands for (CH₂)_(q), whereby q=0 oris an integer from 1 to
 12. 11. Estratrienes according to one of thepreceding claims, wherein Y is a direct bond between X and Z or anSO_(n) group, whereby n=0, 1 or
 2. 12. Estratrienes according to one ofthe preceding claims, wherein Z is a straight-chain or branched-chainC₁--C₇-alkylene radical, which is at least partially fluorinated. 13.Estratrienes according to one of the preceding claims, wherein E standsfor CF₃ or for pentafluorophenyl.
 14. Estratrienes according to one ofthe preceding claims, wherein Z—E stands for C₂F₅, C₃F₇, C₄F₉ or forC₆F₅.
 15. Estratrienes with general formula I, namely11βFluoro-7α-{5-[methyl(7,7,8,8,9,9,9-heptafluorononyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide11β-Fluoro-7α-{5-[methyl(8,8,9,9,10,10,10-heptafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide(RS)-11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]-pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide11β-Fluoro-7α-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide11β-Fluoro-7α-{5-[methyl(9,9,10,10,10-pentafluorodecyl)amino]pentyl-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide11β-Fluoro-7α-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,9-heptafluorononyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol17α-Ethinyl-11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)-amino]pentyl}-estra-1,3,5(10)-triene-3,17β-diol17α-Ethinyl-11β-fluoro-3-(2-tetrahydropyranoyloxy)-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-estra-1,3,5(10)-trien-17β-ol11β-Fluoro-3-(2-tetrahydropyranyloxy)-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-trien-17β-ol 11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-trifluoromethylestra-1,3,5(10)-triene-3,17β-diol11β-Fluoro-7α-{5-[methyl(6,6,7,7,8,8,8-heptafluorooctyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol11β-Fluoro-7α-{5-[methyl(3,8,9,9,10,10,10-heptafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol11β-Fluoro-7α-{5-[methyl(6,6,7,7,8,8,9,9,10,10,10-undecafluorodecyl)amino]-pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol11β-Fluoro-7α-{5-[methyl(5,5,6,6,7,7,8,8,8-nonafluorooctyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol11β-Fluoro-7α-{5-[methyl(9,9,10,10,11,11,11-heptafluoroundecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol11β-Fluoro-7α-{5-[methyl(9,9,10,10,10-pentafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol16. 17β-Oxy-estratrienes with general formula II

in which Hal stands for F or Cl and is bonded in 11β-position to theestratriene skeleton, R³ stands for hydrogen, C₁--C₄-alkyl,C₁--C₄-alkanoyl or a cyclic C₃--C₇-ether with an O atom, R_(17′) standsfor hydrogen, C₁--C₄-alkyl or for C₁--C₄-alkanoyl and is bonded in17β-position to the estratriene skeleton, and SK stands for the groupingU—V—W—X—Y—Z—E, whereby this grouping is bonded via U in 7α-position tothe estratriene skeleton, and whereby U, V, X, Y, Z and E have themeanings that are indicated in claims 1-15, provided that W stands foran N⁺(O⁻)(R⁶) group or for an azolidinylene-N-oxide ring, whereby theazolidinylene-N-oxide ring includes at least one C atom of grouping X,in which R⁶ has the meaning that is indicated in one of claims 1-15. 17.17β-Oxy-estratrienes with general formula II, namely11β-Fluoro-7α-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}estra-1,3,5(10)-triene-3,17β-doilN-oxide11β-Fluoro-7α-[5-(methyl{3-[(2,3,4,5,6-pentafluorophenyl)sulfanyl]propyl}-amino)pentyl]estra-1,3,5(10)-triene-3,17β-doilN-oxide11βFluoro-7α-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]propyl}amino)-pentyl]estra-1,3,5(10)-triene-3,17β-diolN-oxide11β-Fluoro-7α-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]propyl}amino)-pentyl]estra-1,3,5(10)-triene-3,17β-doilN-oxide11βFluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-triene-3,17β-diol N-oxide(S)-11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide(R)-11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diolN-oxide11β-Fluoro-7α-{5-[methyl(9,9,10,10,10-pentyfluorodecyl)amino]pentyl}estra-1,3,5(10)-triene-3,17β-diolN-oxide.
 18. 17-Oxo-estratrienes with general formula III

in which Hal stands for F or Cl and is bonded in 11β-position to theestratriene skeleton, R³ stands for hydrogen, C₁--C₄-alkyl,C₁--C₄-alkanoyl or a cyclic C₃--C₇-ether with an O atom, and SK standsfor the grouping U—V—W—X—Y—Z—E, whereby this grouping is bonded via U in7α-position to the estratriene skeleton and whereby U, V, X, Y, Z and Ehave the meanings that are indicated in claims 1-15, provided that Wstands for an N⁺(O⁻)(R⁶) group or for an azolidinylene-N-oxide ring,whereby the azolidinylene-N-oxide ring includes at least one C atom ofgrouping X, in which R⁶ has the meaning that is indicated in one ofclaims 1-15.
 19. 17-Oxo-estratrienes with general formula III, namely11β-Fluoro-7α-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]propyl}-amino)pentyl]estra-1,3,5(10)-trien-3-ol-17-oneN-oxide11β-Fluoro-7α-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]propyl}amino)-pentyl]estra-1,3,5(10)-trien-3-ol-17-oneN-oxide11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-trien-3-ol-17-oneN-oxide
 20. Use of the 17α-alkyl-17β-oxy-estratrienes with generalformula I according to one of claims 1-15 for the production ofpharmaceutical agents.
 21. Pharmaceutical preparations that contain atleast one 17α-alkyl-17β-oxy-estratriene with general formula I accordingto one of claims 1-15 as well as at least one pharmaceuticallycompatible vehicle.